bims-mideyd 2025-05-11 papers

Int J Mol Sci. 2025 Apr 14. pii: 3704. [Epub ahead of print]26(8):

Liraglutide Attenuates FFA-Induced Retinal Pigment Epithelium Dysfunction via AMPK Activation and Lipid Homeostasis Regulation in ARPE-19 Cells.

Sing-Hua Tsou, Kai-Shin Luo, Chien-Ning Huang, Edy Kornelius, I-Ting Cheng, Hui-Chih Hung, Yu-Chien Hung, Chih-Li Lin, Min-Yen Hsu.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, and it is characterized by oxidative stress, lipid dysregulation, and dysfunction of the retinal pigment epithelium (RPE). A hallmark of AMD is the presence of drusen, extracellular deposits rich in lipids, proteins, and cellular debris, which are secreted by the RPE. These deposits impair RPE function, promote chronic inflammation, and accelerate disease progression. Despite advancements in understanding AMD pathogenesis, therapeutic strategies targeting lipid dysregulation and oxidative damage in RPE cells remain limited. This study evaluated the effects of liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), on free fatty acid (FFA)-induced damage in ARPE-19 cells, a widely used in vitro model of RPE dysfunction. FFA treatment induced lipid droplet accumulation, oxidative stress, and epithelial-mesenchymal transition (EMT), which are processes implicated in AMD progression. Liraglutide significantly reduced lipid droplet accumulation, mitigated oxidative stress, and suppressed EMT, as demonstrated by high-content imaging, immunocytochemistry, and molecular assays. Mechanistic analyses revealed that liraglutide activates AMP-activated protein kinase (AMPK), enhancing lipophagy and restoring lipid homeostasis. Furthermore, liraglutide influenced exosome secretion, altering paracrine signaling and reducing EMT markers in neighboring cells. These findings underscore liraglutide's potential to address critical mechanisms underlying AMD pathogenesis, including lipid dysregulation, oxidative stress, and EMT. This study provides foundational evidence supporting the development of GLP-1 receptor agonists as targeted therapies for AMD.

Keywords: AMP-activated protein kinase (AMPK); epithelial-mesenchymal transition (EMT); free fatty acid (FFA); lipid droplet (LD); liraglutide; retinal pigment epithelium (RPE)

DOI: https://doi.org/10.3390/ijms26083704

Free Radic Res. 2025 May 09. 1-21

Luteolin protects human ARPE-19 retinal pigment epithelium cells from blue light-induced phototoxicity through activation of Nrf2/Keap1 signaling.

Ryo Hayakawa, Takeshi Ishii, Taiki Fushimi, Yuki Kamei, Ai Yamaguchi, Kenji Sugimoto, Hitoshi Ashida, Mitsugu Akagawa.

Age-related macular degeneration (AMD), a serious physical and mental health problem worldwide, is the leading cause of irreversible, severe vision impairment and loss in older people. AMD is associated with multiple risk factors, many of which are closely linked to increased oxidative stress. Some studies have suggested that long-term and excessive exposure to blue light may be a potential risk factor for the development or progression of AMD. Recently, we demonstrated that blue light irradiation caused oxidative stress in all-trans-retinal (atRAL)-exposed human ARPE-19 retinal pigment epithelium cells by generating singlet oxygen (1O2), leading to apoptotic cell death. Luteolin, a flavonoid found in various edible plants, has been reported to possess divergent health-promoting properties including anti-oxidative and chemopreventive effects by up-regulating anti-oxidative and phase II detoxifying enzymes through activation of Keap1/Nrf2 signaling. Herein, we verified the cytoprotective action of luteolin against blue light irradiation using atRAL-exposed ARPE-19 cells. Our results established that luteolin effectively prevented blue light-induced apoptosis of ARPE-19 cells by mitigating oxidative stress. We also confirmed that luteolin suppressed intracellular accumulation of 1O2 and formation of atRAL-derived lipofuscin by increased expression of heme oxygenase-1 and aldehyde dehydrogenase 1A1 through activation of Keap1/Nrf2 signaling. Furthermore, our data implied that the luteolin-provoked activation of Keap1/Nrf2 signaling might be due to covalent binding of luteolin o-quinone to the critical cysteinyl thiol in Keap1. The present results suggest that luteolin could be helpful in the prevention and amelioration of blue light-induced retinal degeneration, including AMD.

Keywords: Luteolin; age-related macular degeneration; blue light; retinal pigment epithelium cells; singlet oxygen

DOI: https://doi.org/10.1080/10715762.2025.2503832

Int J Mol Sci. 2025 Apr 15. pii: 3735. [Epub ahead of print]26(8):

The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration.

Xiyuan Liu, Zhaoze Ni, Jing Zhang, Xiaoyan Lin, Chenxin Wu, Yuyang Wu, Lingqin Dong, Zongduan Zhang, Zai-Long Chi.

The retinal pigment epithelium (RPE) serves as a critical guardian of subretinal homeostasis, with its dysfunction implicated in major retinal pathologies, including age-related macular degeneration (AMD) and retinitis pigmentosa. While cellular senescence has emerged as a key driver of RPE degeneration, the molecular mechanisms underlying this process remain incompletely defined. Emerging evidence implicates dual-specificity phosphatase 4 (DUSP4) in cellular stress responses through its antioxidant and anti-inflammatory capacities, yet its role in RPE pathophysiology remains unexplored. Our study reveals a compensatory increase in DUSP4 expression during AMD-associated RPE senescence. To functionally characterize this observation, we knocked down DUSP4 in the RPE of mice via subretinal injection of AAV-shDUSP4. In a sodium iodate-induced dry AMD model, mice with DUSP4 knockdown presented more severe visual impairment than control mice did. To further investigate the molecular mechanism, stable DUSP4-knockout cell lines were constructed via CRISPR/Cas9 technology. The high expression of senescence markers in the DUSP4-knockout cell lines was reversed by DUSP4 overexpression. Furthermore, DUSP4 coordinates the modulation of cell cycle, stress response, and pro-inflammatory signaling by inhibiting the p53, p38, and NF-kB pathways. These findings establish DUSP4 as a multi-functional regulator of RPE senescence. Our work not only elucidates a novel DUSP4-dependent mechanism in AMD pathogenesis but also highlights its therapeutic potential for preserving RPE function in AMD.

Keywords: age-related macular degeneration; dual-specificity phosphatase 4; retinal pigment epithelium; senescence

DOI: https://doi.org/10.3390/ijms26083735

Int J Mol Sci. 2025 Apr 08. pii: 3463. [Epub ahead of print]26(8):

Role of Oxidative Stress and Inflammation in Age Related Macular Degeneration: Insights into the Retinal Pigment Epithelium (RPE).

María Elena Ochoa Hernández, Lidianys María Lewis-Luján, María Guadalupe Burboa Zazueta, Teresa Del Castillo Castro, Enrique De La Re Vega, Juan Carlos Gálvez-Ruiz, Sergio Trujillo-López, Marco Antonio López Torres, Simon Bernard Iloki-Assanga.

Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide, characterized by the accumulation of extracellular drusen deposits within the macula. The pathogenesis of AMD is multifactorial, involving oxidative stress, chronic inflammation, immune system dysregulation, and genetic predisposition. A key contributor to disease progression is the excessive accumulation of reactive oxygen species (ROS), which damage retinal pigment epithelium (RPE) cells and disrupt cellular homeostasis. Additionally, immunosenescence and chronic low-grade inflammation exacerbate AMD pathology, further impairing retinal integrity. Despite ongoing research, effective therapeutic options remain limited, and there is no definitive cure for AMD. This review explores the intricate molecular mechanisms underlying AMD, including the role of oxidative stress, chronic inflammation, and genetic factors in RPE dysfunction. Furthermore, we highlight potential therapeutic strategies targeting these pathways, as well as the emerging role of bioinformatics and artificial intelligence in AMD diagnosis and treatment development. By improving our understanding of AMD pathophysiology, we can advance the search for novel therapeutic interventions and preventative strategies.

Keywords: age-related macular degeneration (AMD); bioinformatics; immunosenescence; inflammation; oxidative stress; retinal pigment epithelium (RPE)

DOI: https://doi.org/10.3390/ijms26083463

Int Ophthalmol. 2025 May 09. 45(1): 183

MiR-6837-3p protected retinal epithelial cells from oxidative stress by targeting E2F6.

Xin Zhao, Xinru Chen, Xiangyang Xin.

AIM: The mechanism of age-related macular degeneration (AMD) is a complex illness that is not fully understood. Therefore, the aim of this study was to investigate the expression patterns of miR-6837-3p in retinal epithelial cells.
METHODS: H2O2 was used to treat ARPE-19 cells for 2, 4 and 6 h to mimic the in vivo environment of AMD. MiR inhibitors and mimics were used to inhibit or overexpress miR-6837-3p in H2O2-treated ARPE-19 cells, respectively. Then, CCK8 assay, flow cytometry, and wound healing assays were conducted to assess the effects of miR-6837-3p on the behaviors of ARPE-19 cells, including cell growth, apoptosis, cycle progression, and migration. Finally, microRNA database prediction and luciferase reporter assays were used to demonstrate that miR-6837-3p targets the downstream gene E2F6.
RESULTS: H2O2 induced a decrease in cell viability and an increase in ROS levels in a time-dependent manner. Additionally, overexpression of miR-6837-3p increased cell viability and suppressed apoptosis in ARPE-19 cells treated with H2O2. Meanwhile, increased miR-6837-3p promoted cell cycle progression and cell migration of ARPE-19 cells. Finally, miR-6837-3p exerted anti-apoptosis and anti-oxidative stress effects by inhibiting the expression of E2F6 in ARPE-19 cells.
CONCLUSIONS: The MiR-6837-3p/E2F6 axis might be a target for the treatment of AMD to improve ARPE-19 cell function.

Keywords: ARPE-19; Age-related macular degeneration; Apoptosis; Cell cycle; E2F6; MiR-6837-3p

DOI: https://doi.org/10.1007/s10792-025-03540-3